Deciphering the development of synovial joints in the limbs: Recent discoveries and clinical implications

The synovial joints are essential for skeletal function and dexterity and do so by virtue of their components and structure. The capsule protects and insulates the joint from the surrounding environment, articular cartilage provides mechanical resilience and endurance, the ligaments stabilize motion, and the synovial cavity and fluid sustain frictionless sliding. These and other fundamental aspects of synovial joint biology are well known and recognized. However, how the joints form during embryogenesis and acquire their components and functional attributes remains unclear. Happily, the last few years of research have provided new insights into limb joint development. In particular, new light has been shed on: morphogenetic mechanisms establishing the mesenchymal interzone which is the cradle of joint tissue progenitors; spatio-temporal processes endowing the joint progenitors with distinct developmental and tissue forming potentials; osmoregulatory and hydraulic forces set by Na/K-ATPase ion pumps that bring about joint cavitation and fluid accrual; cellular and signaling mechanisms establishing articular cartilage's zonal organization; and potentials of embryonically-derived progenitors residing in adult joints to engage in repair. This review describes and comments on those new studies, frames them within the broader field of joint research, and identifies lingering questions. Clinically, the treatment of joint disease remains ineffective and new directions and strategies are needed to move forward. Studies on synovial joint development are poised to provide such new directions and bring about future regenerative tools based on principles and mechanisms of developmental biology. This review is meant to highlight the potentials of such basic-to- translational-to-clinical strategies and provides an overall framework for research goals ahead.